Disorders of the immune system are responsible for a multitude of human diseases which result in serious effects on the quality of life of individuals suffering from such disorders as well as of their family members. These disorders may stem either from an overproduction or underproduction of certain components of the immune system. Nowhere are the far reaching economic and health consequences of immune disorders better illustrated than in the recurrent infections in antibody-deficient individuals, and in the autoimmune disease systemic lupus erythematosus.
A) Recurrent Infection In Antibody-Deficient Individuals
Recurrent infection in individuals who are deficient in immunoglobulins with polysaccharide-coated bacterial pathogens (e.g., Haemophilus influenzae, Streptococcus pneumoniae, and group B streptococci) is a serious problem with significant clinical and economic consequences. For example, children with normal levels of immunoglobulins but subnormal levels of the IgG2 subclass have been found to have recurrent sinopulmonary infections as well as sepsis with polysaccharide encapsulated bacteria such as H. influenzae type b and pneumococcus (Shackelford et al. (1986) J. Pediat. 108:647; Umetsu et al. (1995) N. Engl. J. Med. 313:1247). In spite of the availability of antibiotics, the mortality of pneumococcal bacteremia in the last four decades has not dropped below 25%. [DeVelasco et al. (1995) Microbiol. Rev. 59:591-603]. In addition, because low serum IgG2 levels in adults are associated with failure to make an antibody response to polysaccharide vaccines (Umetsu et al. (1985) supra; Wasserman (1990) Pediatr. Infect. Dis. 9:424). IgG2-deficient adults are not protected against subsequent infection with polysaccharide-coated bacteria. This ineffective vaccination results in a serious waste of economic resources both at the level of the health worker whose efforts are better spent on individuals who are responsive to such immunization, as well as at the level of the IgG2-deficient individual whose subsequent infection results in repeated absence from work and a deterioration in the quality of life.
Available methods for the treatment of IgG2-deficiency in adults are limited to the administration of intravenous immunogobulin (IVIG). However, recent outbreaks of hepatitis in patients treated with IVIG has cast serious doubts on the usefulness of this approach. Furthermore, while the immunodeficient XID mouse may provide an animal model to evaluate immunization protocols against polysaccharide-coated pathogenic bacteria, the XID mouse is an unsuitable model. The XID mouse contains a missense mutation in the amino terminal of the Bruton's tyrosine kinase (btk) gene [Thomas et al., (1993) Science 261:355-358; Rawlings, et al., (1993) Science 261:358-361]. Although the XID mouse produces subnormal levels of antibodies in response to immunization with polysaccharides or hapten-polysaccharide conjugates, it is unclear whether this deficiency is the result of a deficiency in the production of IgM or some other immunoglobulin deficiency. This is due, in part to the expression of lowered serum levels of both IgM and IgG3 in the XID mouse [I. Scher, (1982) Adv. Immunol. 33:1]. Furthermore, while the levels of IgG3 in the XID mouse are reduced in relation to the wild type mouse from which they are derived, the XID mouse expresses significant levels of IgG3 both constitutively and following immunization with polysaccharide antigens [I. Scher, (1982) Adv. Immunol. 33:1; Thomas et al., (1993) Science 261:355-358]. While XID mice contain a single genetic defect, failure to attribute the pathological manifestations observed in these mice to a single underlying immunological defect precludes rational drug design.
B) Systemic Lupus Erythematosus (SLE)
Systemic lupus erythematosus (SLE) is a debilitating autoimmune disease with an annual incidence of about seven cases per 100,000. The clinical manifestations of SLE include fever, rash, arthritis, acute hemolytic anemia, thrombocytopenic purpura, pericarditis and a predisposition to bacterial infections. More importantly, patients with active SLE suffer from varying degrees of renal dysfunction, which range from proteinuria and pyuria to decreased glomerular filtration rate leading to nitrogen retention, electrolyte disturbance and acidosis. Renal disease is the most frequent source of morbidity and mortality in these patients.
While several mechanisms which result in autoimmune reactions have been proposed, the precise physiological mechanisms of SLE are not entirely understood. In particular, the determination of the biochemical and immunological mechanisms underlying renal disease is complicated by the multitude of pathophysiological symptoms associated with renal tissue damage. For example, renal disease may be attributed to any one or a combination of the associated elevation in circulating immune complexes, or to complement components and immunoglobulins which are found in diseased kidney tissue.
The treatment of SLE in general, and the associated renal dysfunction in particular, focuses on the alleviation of the general symptoms of the disease using one or a combination of two modalities, i.e., non-pharmacological treatment and pharmacological treatment. Non-pharmacological treatment includes periods of bed rest, avoiding exposure to sunlight, avoiding oral contraceptives and intrauterine devices, and long-term hemodialysis and kidney transplantation for the treatment of end-stage renal disease. Non-pharmacological treatment is often used as an adjunct to pharmacological treatment.
Pharmacological treatment includes the use of anti-inflammatory agents (e.g., salicylate), antimalarial drugs (e.g., chloroquine and hydroxychloroquine), corticosteroids, and cytotoxic drugs (e.g., cyclophosphamide). Unfortunately, most of the pharmacological approaches are controversial because few carefully controlled trials have been conducted. Moreover, many of the commonly used pharmacological agents have numerous side effects. For example, some patients with active SLE may experience aspirin-induced hepatitis. Antimalarial drugs may cause an irreversible retinopathy which leads to blindness, as well as skeletal muscle myopathy, cardiomyopathy and peripheral neuropathy. In addition, long-term corticosteroid use suffers from well known toxic effects. Attempts to reduce toxicity with alternate day dosage schedules are often unsatisfactory. Furthermore, the use of corticosteroids has not been proved to alter the ultimate course or outcome of glomerulonephritis in SLE. Treatment with pharmacological agents is further exacerbated by the nonresponsiveness by many patients with severe SLE who, paradoxically, are in most need of treatment.
To overcome ethical considerations (e.g., health safety, availability of willing subjects, etc.) which hamper the development of therapeutic agents for SLE-associated renal disease, animals have been proposed as a useful model for screening candidate therapeutic modalities. Several animals which bear gene alterations in humoral immune responsiveness are available [see e.g., Torres et al. (1996) Science 272:1804-1808; Leitges et al. (1996) Science 273:788-791; Shachar et al. (1996) Science 274:106-108; Steeber et al. (1996) J. Immunol. 157:4899-4907]. An example of such animals is the inbred MRL/MpJ-lpr/lpr mouse strain has been used as a model for SLE in humans. MRL/MpJ-lpr/lpr mice express unusual levels of cryoglobulins, primarily of the IgG3 subclass, elevated titers of immune complexes, and a diffuse glomerulonephritis. While the MRL/MpJ-lpr/lpr mouse exhibits some of the pathological abnormalities associated with renal disease in patients suffering from SLE, this animal is not suitable for the rational testing of drugs to alleviate or treat renal disease in SLE patients. This is due, in part, to the presence in the MRL/MpJ-lpr/lpr mouse of several genetic, immunologic and metabolic abnormalities. Because it would be unclear which, if any, of the genetic, immunologic and metabolic abnormalities exhibited by the MRL/MpJ-lpr/lpr mouse are affected by treatment for renal disease with a test drug, it is not feasible to rationally design drugs which target specifically those pathways which are modulated by that drug.
Thus, to date both non-pharmacological and pharmacological treatments provide unsatisfactory approaches to treating renal dysfunction associated with SLE because these approaches are generally ineffective, their effects are inconsistent, and are directed to alleviating the general symptoms of SLE, rather than specifically addressing the treatment of the most prevalent source of morbidity and mortality in SLE patients, i.e., renal disease. Moreover, no suitable animal models are currently available to rationally design drugs which target specific immunological mechanisms which cause nephritis in individuals suffering from SLE disease.
What is needed is a better model of these diseases. This model should be amenable to the testing of chemical compounds in the treatment of SLE-associated renal disease and of infection with bacterial pathogens.